Cancer is the leading cause of mortality in the Western countries. A large number of chemotherapeutic agents have been developed over the last 50 years to treat cancers. The majority of chemotherapeutic agents can be classified into one of the following groups: alkylating agents, antimetabolites, anthracyclines, plant alkaloids, topoisomerase inhibitors, and antitumour agents. All of these drugs affect cell division or DNA synthesis and function in some way.
The effectiveness of particular chemotherapeutic agents varies between cancers, between patients and over time in individual patients. Cancerous cells exposed to a chemotherapeutic agent may develop resistance to such an agent, and quite often cross-resistance to several other antineoplastic agents as well. Moreover, the narrow therapeutic index of many chemotherapeutic agents further limits their use. Accordingly, it is often necessary to change treatments of patients with cancer if the first or second line therapy is not sufficiently effective or ceases to be sufficiently effective. In many cases combinations of particular treatments have been found to be particularly effective.
These chemotherapeutics agents, 5-Fu included, can be used alone but it is common that clinical regimes incorporate a combination. Indeed combined chemotherapy has shown promising results by improving the response rates in patients by acting on the tumors through different pathways. Nevertheless many patients still cannot be treated through these regimes because of drug resistance, either acquired or inherent.
Further, the choice of chemotherapy is further complicated by cancer type and, for example, whether or not the cancer is associated with a p53 mutation. For example, as described in WO2005/053739, whereas the combination of platinum based chemotherapeutics with antiFas antibodies was shown to have a synergistic cytotoxic effect in tumours with wild type p53, such synergy was not seen in p53 mutant cells.
5-Fu, CPT-11 and oxaliplatin remain front line therapies, but the development of non responsive tumours or chemotherapy resistant cancer remains a major obstacle to successful chemotherapy. Due to the importance of early treatment of cancers, there is a clear need for tools which enable prediction of whether a particular therapy, either single or combination, will be effective against particular tumours in individual patients. Moreover, there remains the need for new treatment regimes to increase the repertoire of treatments available to the physician.
As described in the inventors' copending international application PCT/GB2007/050623, the present inventors have investigated proteins upregulated in response to treatment with different classes of chemotherapy and have surprisingly shown that a variety of genes encoding peptide growth factors of the Epidermal Growth Factor (EGF) family are overexpressed in a number of different tumour cell line models of cancer from a number of different types of cancer following in vivo challenge with different physiologically relevant doses of different classes of chemotherapy.
The inventors have also shown that combinations of inhibitors of different EGFs resulted in a surprisingly dramatic reduction in tumour cell growth and proliferation compared to the reduction when inhibitors of a single EGF were tested.